ABSTRACT The BXSB Y chromosome-linked mutant gene, Yaa, promotes autoimmune responses in mice predisposed to a lupus-like autoimmune disease. We have previously shown that a cognate interaction of T cells with B cells expressing the Yaa gene appears to be responsible for the accelerated production of autoantibodies. To investigate whether T cells that provide help for autoantibody production by Yaa+ B cells need to express the Yaa gene, we have made radiation bone marrow chimeras containing two sets of T and B cells from mice with or without the Yaa gene and differing by the Thy-1 and Igh allotypes. We then determined autoantibody production following the selective elimination of T cells of Yaa+ origin by treating mice with allele-specific anti-Thy-1 monoclonal antibody. Our results demonstrated that the selective production of autoantibodies by Yaa+ B cells in Yaa(+)-Yaa- double bone marrow chimeras can be mediated as efficiently by T cells from non-autoimmune mice lacking the Yaa gene as by T cells from autoimmune mice bearing the Yaa gene. This indicates that T cells from non-autoimmune Yaa- mice are capable of providing help for autoimmune responses by collaborating with Yaa+ B cells. These data thus strongly suggest that the Yaa gene defect is not functionally expressed in T cells, but only in B cells, and contrast with parallel experiments in the lpr model, in which defects of the Fas antigen in both T and B cells are crucial for the lpr gene-mediated promotion of autoantibody production.

[Show abstract][Hide abstract]ABSTRACT: Interleukin 21 (IL-21) is a pleiotropic cytokine produced by CD4 T cells that affects the differentiation and function of T, B, and NK cells by binding to a receptor consisting of the common cytokine receptor gamma chain and the IL-21 receptor (IL-21R). IL-21, a product associated with IL-17-producing CD4 T cells (T(H)17) and follicular CD4 T helper cells (T(FH)), has been implicated in autoimmune disorders including the severe systemic lupus erythematosus (SLE)-like disease characteristic of BXSB-Yaa mice. To determine whether IL-21 plays a significant role in this disease, we compared IL-21R-deficient and -competent BXSB-Yaa mice for multiple parameters of SLE. The deficient mice showed none of the abnormalities characteristic of SLE in IL-21R-competent Yaa mice, including hypergammaglobulinemia, autoantibody production, reduced frequencies of marginal zone B cells and monocytosis, renal disease, and premature morbidity. IL-21 production associated with this autoimmune disease was not a product of T(H)17 cells and was not limited to conventional CXCR5(+) T(FH) but instead was produced broadly by ICOS(+) CD4(+) splenic T cells. IL-21 arising from an abnormal population of CD4 T cells is thus central to the development of this lethal disease, and, more generally, could play an important role in human SLE and related autoimmune disorders.

Proceedings of The National Academy of Sciences - PNAS. 01/2009; 106(5):1518-1523.

[Show abstract][Hide abstract]ABSTRACT: Systemic lupus erythematosus is a multifactorial autoimmune disease which has been associated with several genetic, hormonal and environmental factors. TLRs are a group of innate immune system receptors and have been linked strongly to SLE development. Several lines of evidence support the significant role of TLR7 in initiation and progression of autoimmunity. The common presence of anti-β2GPI antibodies in SLE patients and the antagonizing effect of these antibodies on the physiologic roles of the β2GPI may suggest a function for this protein in the pathogenesis of SLE. In addition, a recent in vitro report on the role of anti-β2GPI antibodies in translocation and activation of TLR7 raised the suspicion about the possible interactions between TLR7 and β2GPI in development of SLE. By deleting the β2GPI gene from a TLR7-dependent mouse model of SLE, BXSByaa, we have shown that the absence of this protein causes acceleration of the disease development in these mice with presentation of a more severe phenotype including, large lymphadenopathy huge splenomegaly and increased mortality. Histological and serological studies showed that the absence of β2GPI led to formation of a very severe nephritis in BXSByaa mice and production of a high titer of autoantibodies and inflammatory cytokines including BAFF and IFN-I. Flowcytometery analysis also showed a significant proportional increase in the population of the immune cells involved in the pathogenesis of SLE. In vitro experiments did not show any direct inhibitory or enhancing interaction between β2GPI and TLR7. But we have shown that in the absence of β2GPI there is decreased phagocytosis of apoptotic cells by macrophages in vivo. Impaired phagocytosis has been proposed to be one of the main mechanisms involved in the pathogenesis of SLE. As one of the posttranslational modification reactions, oxidization of antigens has been linked to increase in their immunogenecity. Here we have shown that disrupting of the β2GPI gene causes an increase in the serum titer of anti-oxidized RNA antibodies. This observation which can be a reflection of higher titer of oxidized-RNA may imply the protective role of β2GPI in preventing the occurrence of posttranslational modifications of nucleic acid-containing antigens under pathologic conditions like oxidative stress. These findings may open new areas of research to further investigate the possible roles of β2GPI in inflammation and innate immunity and the autoimmune pathologies that may arise upon disruption of its function.

[Show abstract][Hide abstract]ABSTRACT: Chronic inflammatory conditions, such as in autoimmune disease, can disturb immune cell homeostasis and induce the expansion of normally rare cell populations. In our analysis of various murine models of lupus, we detect increased frequency of an uncommon subset identified as NK1.1+CD11c+CD122+MHC class II+. These cells share characteristics with the NK cell lineage and with cells previously described as IFN-producing killer dendritic cells: 1) they depend on IL-15 and express E4BP4; 2) they are cytotoxic and produce type I and type II IFN upon activation; and 3) they are efficient APCs both through MHC class II expression and in cross-presentation to CD8s. These atypical NK cells are responsive to TLR stimulation and thus are most abundant in mice with high copy number of the Tlr7 gene. They are highly proliferative as assessed by in vivo BrdU incorporation. In adoptive transfer experiments they persist in high numbers for months and maintain their surface marker profile, indicating that this population is developmentally stable. Gene expression analyses on both mRNA and microRNAs show a modified cell cycle program in which various miR-15/16 family members are upregulated, presumably as a consequence of the proliferative signal mediated by the increased level of growth factors, Ras and E2F activity. Alternatively, low expression of miR-150, miR-181, and miR-744 in these cells implies a reduction in their differentiation capacity. These results suggest that cells of the NK lineage that undergo TLR stimulation might turn on a proliferative program in detriment of their full differentiation into mature NK cells.

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